My academic career goal is to develop a multidisciplinary program to study the complex genetic etiology of cancer, improve the ability to identify individuals who are predisposed to develop cancer, and transfer this knowledge to cancer prevention and control strategies. The Preventive Oncology Academic Award will provide me with the means to take two steps in implementing this goal. First, I will obtain additional education in cancer genetics and practical experience in molecular genetics that will augment previous training in statistics, epidemiology and human genetics. Second, I will undertake a research program that uses a multidisciplinary strategy to understand the genetic etiology of breast cancer. The unifying biological hypothesis of the proposed research is that a set of somatic genetic changes, possibly the result of environmental exposures, must occur before an individual with an inherited genetic predisposition will develop breast cancer. This hypothesis is supported by the fact that breast cancer aggregates in families but does not usually segregate in a Mendelian manner. Two research projects are proposed here to study this hypothesis. The first project will relate genotypic variability with breast cancer occurrence and age of breast cancer onset. The genes to be studied in this project encode the phase I and II detoxification enzymes that are responsible for the metabolism of environmental carcinogens and steroid hormones. The goals of this project are to determine a) whether these genes are involved in the genetic etiology of breast cancer, and b) whether these genes provide additional information about breast cancer predisposition beyond that provided by traditional epidemiologic risk factors. The results of this first project will contribute information about the utility of these genes in primary breast cancer prevention strategies. The second project will study somatic genetic changes in cancer predisposition directly by assessing the contribution of tumor genotypes in genetic linkage analyses. Somatic genetic changes measured by loss of constitutional heterozygosity at tumor suppressor loci will be analyzed. The goals of this project are a) to understand and use somatic genetic changes to identify genes that predispose an individual to develop breast cancer, and b) to identify families and individuals who carry these genes. The results of this second project will improve the power to detect genetic markers of breast cancer risk and facilitate the identification of individuals with increased breast cancer risk.